What is the definition, pathophysiology, symptoms, diagnosis, and treatment of asthma according to the Global Initiative for Asthma (GINA) 2025 guidelines?

Asthma According to GINA 2025 Guidelines

Definition

Asthma is a chronic inflammatory disorder of the airways characterized by three distinct pathophysiologic responses: inflammation, bronchial hyperresponsiveness, and airway remodeling. 1

• The disease manifests as recurrent episodes of coughing, wheezing, breathlessness, and chest tightness, with variable airflow obstruction that is often reversible either spontaneously or with treatment. 2
• The airflow limitation is variable and reversible, distinguishing it from fixed obstructive diseases. 3

Pathophysiology

Core Inflammatory Mechanisms

The fundamental pathophysiology involves chronic airway inflammation that drives three interconnected processes: bronchoconstriction, bronchial hyperresponsiveness, and progressive airway remodeling. 2

• Multiple cellular players orchestrate this inflammation, including mast cells, eosinophils, T lymphocytes, macrophages, and epithelial cells. 2
• Neutrophils play a particularly important role in sudden-onset fatal exacerbations, occupational asthma, and in patients who smoke. 2

Three Mechanisms of Airflow Limitation

Bronchial smooth muscle contracts rapidly in response to allergens, irritants, and other stimuli, representing the most immediately reversible component. 2

• Airways develop an exaggerated bronchoconstrictor response to stimuli that would not affect normal airways (bronchial hyperresponsiveness). 2
• Edema, mucus hypersecretion, and formation of inspissated mucus plugs further limit airflow, with these changes being less immediately reversible than bronchoconstriction alone. 2

Airway Remodeling

Persistent inflammation leads to permanent structural changes including sub-basement membrane fibrosis, smooth muscle hypertrophy, epithelial cell injury and shedding, angiogenesis, and mucus gland hyperplasia. 2

• These structural changes explain why airflow limitation may become incompletely reversible in some patients despite aggressive treatment. 2

Genetic and Environmental Factors

There is a strong genetic component, with 80% of children with two asthmatic parents developing asthma. 1

• Gene-environment interactions are critical, with environmental exposures during immune system development being essential. 2, 1
• In utero exposures such as maternal smoking increase childhood asthma risk in a dose-dependent pattern. 2, 1

Phenotypic Variation

• Different asthma phenotypes exist with varying patterns of inflammation: approximately 80-85% of cases are classified as T2-high asthma (eosinophilic), while only 15-20% are T2-low asthma (neutrophilic). 4
• T2-high asthma is driven by eosinophils, mast cells, and Th2 cells releasing IL-4, IL-5, and IL-13, promoting IgE production. 4
• T2-low asthma is characterized by neutrophilic inflammation driven by Th1 and Th17 immune responses, often present in older adults, smokers, and those with more severe disease. 4

Symptoms

Cardinal Symptoms

The hallmark symptoms are wheeze, shortness of breath, chest tightness, and cough—none of which is specific for asthma alone. 3

Characteristic Patterns

These symptoms are characteristically variable, intermittent, worse at night, and provoked by triggers including exercise. 3

• Symptoms can be triggered by specific stimuli including allergens, irritants, exercise, cold air, and viral infections. 2
• When cough is the predominant symptom without wheeze, this is referred to as cough variant asthma. 3
• Symptoms can be present even in patients with mild asthma when they have few symptoms. 2

Additional Clinical Clues

• Personal or family history of asthma or other atopic conditions (eczema, allergic rhinitis). 3
• Worsening of symptoms after exposure to recognized triggers such as pollens, dust, feathered or furry animals, exercise, viral infections, chemicals, and environmental tobacco smoke. 3
• Worsening after taking aspirin/NSAIDs or use of β-blockers. 3

Diagnosis

Diagnostic Approach

Asthma is a clinical diagnosis requiring episodic symptoms of airflow obstruction PLUS demonstration of reversible airway obstruction using spirometry. 1

• The diagnosis is clinical; there is no confirmatory diagnostic blood test, radiographic or histopathological investigation. 3
• Diagnosis should be based on episodic symptoms of airflow obstruction, including difficulty breathing, chest tightness, cough, wheezing, and symptoms triggered by exercise or allergens. 1

Objective Testing Requirements

Spirometry is mandatory for initial assessment, evaluation of treatment response, and assessment every 1-2 years. 1

• The 2024 GINA report recommends five methods to objectively confirm excessive variability in lung function, including positive bronchodilator reversibility testing. 3
• During exacerbations, patients will often have wheeze and reduced lung function, either reduced peak flow or an obstructive pattern on spirometry. 3
• Outside acute episodes, there may be no objective signs of asthma. 3
• The presence of wheeze (usually diffuse, polyphonic, bilateral and particularly expiratory) is a cardinal sign and should be documented in clinical notes. 3

When Spirometry is Normal

Bronchoprovocation testing, such as methacholine or histamine challenge, can be useful when asthma is suspected but spirometry is normal. 1

• If peak expiratory flow (PEF) and FEV1 are repeatedly normal in the presence of symptoms, then a diagnosis of asthma must be in doubt. 3

Differential Diagnosis Considerations

• Differentiation must be made from localized airway obstruction (tumor, foreign body, vocal cord dysfunction, post-tracheostomy stenosis) versus generalized problems (COPD, bronchiectasis, cystic fibrosis, obliterative bronchiolitis). 3

Treatment

Management Principles

Managing asthma long-term requires four components: assessment and monitoring, patient education, control of environmental factors and comorbid conditions, and medications using a stepwise approach. 1

Pharmacologic Therapy

Inhaled corticosteroids are the standard of care for persistent asthma, with combination therapy with long-acting beta-agonists for patients who do not respond to inhaled corticosteroids alone. 1

Key Treatment Changes in GINA 2021

Asthma in adults and adolescents should NOT be treated solely with short-acting β2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse. 5

• GINA 2021 divides treatment into two tracks for adults and adolescents. 5
• Track 1 (preferred): Low-dose ICS-formoterol as the reliever at all steps—as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (MART) in Steps 3-5. 5
• Track 2 (alternative): As-needed SABA across all steps, plus regular ICS (Step 2) or ICS-LABA (Steps 3-5). 5
• Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone. 5

Advanced Therapies for Severe Asthma

For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. 5

• Novel monoclonal antibody therapies include anti-IgE (omalizumab), anti-IL-5 (mepolizumab, benralizumab), and anti-IL-4/IL-13 (dupilumab) for T2-high asthma. 4
• For T2-low asthma, macrolide antibiotics like azithromycin and other novel therapies are being explored. 4

Transitioning from Oral to Inhaled Corticosteroids

Transitioning from oral corticosteroids to inhaled therapy requires careful monitoring and reduction of prednisone by 2.5 mg weekly during inhaled corticosteroid therapy. 1

Monitoring and Assessment

Spirometry is required for initial assessment, treatment response evaluation, and at least every 1-2 years. 1

• Written action plans with or without peak flow monitoring should be provided. 1
• Regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes. 5

Goals of Asthma Control

The goals are minimal (ideally no) chronic symptoms including nocturnal symptoms, minimal exacerbations, minimal need for relieving bronchodilators, no limitations on activities including exercise, circadian variation in PEF <20%, PEF ≥80% of predicted or best, and minimal adverse effects from medicine. 3

Special Considerations

Stress and psychological factors can amplify airway inflammatory responses, and addressing both psychological stressors and physical triggers is important for patients with stress-related exacerbations or depression. 1, 6

• Consider additional education to improve self-management and coping skills for patients whose asthma is affected by stress or depression. 6
• Environmental control is critical, with maternal smoking being one of the most important modifiable factors. 3

Common Pitfalls to Avoid

• Avoid underdiagnosing asthma by using labels such as "wheezy bronchitis," "recurrent pneumonia," or "reactive airway disease," which can miss the opportunity to treat appropriately. 3
• Do not rely solely on clinical symptoms without objective lung function testing, as this can lead to misdiagnosis. 3, 1
• Antibiotics have no place in the management of uncomplicated asthma. 3